The present invention provides processes for the preparation of saponin compounds, and more specifically, provides processes for the preparation of compounds of formula (1) and to intermediates leading thereto as described herein. The compounds of formula (1) are related to naturally occurring saponins such as OSW-1 and analogues thereof. The compounds are useful as anti-cancer drugs.
Saponins are a large family of naturally occurring glycoconjugate compounds with considerable structural diversity. Saponin OSW-1, 3xcex2,16xcex2,trihydroxycholest-5-en-22-one 16-O-{O-(2-O-(4-methoxybenzoyl)-xcex2-D-xylopryanosyl)-(1-3)-2-O-acetyl-xcex1-arabinopryanoside, is the major component of a small group of cholestane saponins isolated by Sashida et al. (Phytochemistry, 31, 3936, 1992.) from the bulbs of a species of the lily family. OSW-1 is highly toxic against a broad spectrum of malignant tumor cells (Bioorg., Med. Chem. Lett., 7, 633, 1997.) with little toxicity to normal cells in vitro.
Saponins are glycosidic natural plant products, composed of a ring structure (the aglycone) to which is attached one or more sugar chains. The saponins are grouped together based on several common properties. In particular, saponins are surfactants which display hemolytic activity and form complexes with cholesterol. Although saponins share these properties, they are structurally diverse. In particular, the aglycone can be a steroid, triterpenoid or a steroidal alkaloid and the number of sugars attached to the glycosidic bonds vary greatly.
Saponins have been employed as absorption adjuvants in pharmaceutical compositions. For example, U.S. Pat. No. 4,501,734, describes the use of a triterpenoid saponin extract from Sapindus mukurossi Gaertn. to increase absorption of a coadministered beta-lactam antibiotic. Saponins have also been used as immunological adjuvants in vaccine compositions against a variety of diseases including protozoal infections and foot and mouth disease. The saponins typically used as immunological adjuvants are triterpene glycosides extracted from the South American tree, Quillaja saponaria, termed Quil A., see for example, U.S. Pat. No. 5,057,540.
Saponins have also been used in pharmaceutical compositions for a variety of other purposes. For example, U.S. Pat. No. 5,118,671, describes the use of aescin, a saponin obtained from Aesculus hippocastanum seeds, in pharmaceutical and cosmetic compositions as an anti-inflammatory. Similarly, U.S. Pat. No. 5,147,859, discusses the use of Glyccyrrhiza glabra saponin/phospholipid complexes as anti-inflammatory and anti-ulcer agents and U.S. Pat. No. 5,166,139, describes the use of complexes of saponins and aglycons, obtained from Centella asiatica and Terminalia sp., with phospholipids in pharmaceutical compositions. International Publication No. WO 91/04052, published 4 Apr. 1991, discusses the use of solid Quillaja saponaria saponin/GnRH vaccine compositions for immunocastration and immunospaying.
Methods for the synthesis of saponins, and OSW-1 particularly, have received considerable attention recently. Fuchs et al., reported the synthesis of the aglycone portion of OSW-1 (Tetrahedron Lett., 39, 1099, 1998.). Hui et al., reported a convergent total synthesis of OSW-1 from commercially available dehydroisoandrosterone, L-arabinose, and D-xylose in 27 steps in a 6 percent overall yield. (J. Org. Chem., 64, 202, 1999.)
In view of the potential of saponin compounds to treat cancer and related diseases, and the limitations of currently available synthetic methodology, a need exists for efficient processes for the preparation of naturally occurring saponins such as OSW-1 and analogues thereof.
In accordance with the present invention, processes are provided to prepare naturally occurring saponins such as OSW-1 and analogues thereof, having useful biological activity, and particularly activity as anti-cancer agents. Thus, the present invention provides, in embodiments, a process for preparing the compound of formula (1): 
wherein R1 is independently H or a hydroxyl protecting group, R2 is independently-C(xe2x95x90O)xe2x80x94Ar or xe2x80x94C(xe2x95x90O)xe2x80x94CRcxe2x95x90CRdxe2x80x94Ar, wherein Ar is independently aryl or heteroaryl, and Rc and Rd are each independently xe2x80x94H, C1-6alkyl, C1-6alkanoyl, C1-6alkoxycarbonyl, aryl, (aryl)C1-6alkyl, arylcarbonyl, or aryloxycarbonyl, and R10 is, for example, C1-12 alkyl, preferably C2-6 alkyl, and most preferably xe2x80x94CH2xe2x80x94CH(CH3)2, such as, a compound of the formula 
The present invention also provides a process for preparing a saponin intermediate comprising:
reacting, in the presence of a 1,4-addition activating agent, an enone compound of the formula (9) 
xe2x80x83wherein R1 is independently xe2x80x94H or a hydroxyl protecting group, with an alpha-alkoxy vinyl cuprate compound of the formula (8): 
xe2x80x83wherein R3 is an enolic hydroxyl protecting group and R10 is, for example, C1-12 alkyl, preferably C2-6 alkyl, and most preferably xe2x80x94CH2xe2x80x94CH(CH3)2 wherein the compound of the formula (8) is: 
xe2x80x83wherein R3 is an enolic hydroxyl protecting group, to form a compound of the formula (18): 
xe2x80x83wherein R4 is an enolic hydroxyl protecting group, for example, with chemical lability or stability different from the aforementioned R3 enolic hydroxyl protecting group, and R10 is as defined above. Preferably R10 is xe2x80x94CH2xe2x80x94CH(CH3)2, such as, in the compound of the formula: 
The preparative processes of the present invention can also further comprise:
a) converting the above vinyl ether of compound (18) at xe2x80x94OR3 to a corresponding ketal;
b) generating a corresponding enolate at xe2x80x94OR4 of compound (18) wherein R4 is, for example, a metal counter ion; and
c) oxidizing the resulting enolate to an alpha-hydroxy ketone compound of the formula (20): 
The foregoing preparative process of the present invention can further comprise: stereoselectively reducing the ketone of the formula (20) to a 1,2-diol compound of formula (7): 
for example, of the formula: 
In other embodiments, the present invention provides a process for preparing the compound of formula (1): 
wherein R1 can be independently xe2x80x94H or a hydroxyl protecting group, and R2 can be independently xe2x80x94C(xe2x95x90O)xe2x80x94Ar or xe2x80x94C(xe2x95x90O)xe2x80x94CRcxe2x95x90CRdxe2x80x94Ar, wherein Ar can be independently aryl or heteroaryl, and Rc and Rd can independently each be xe2x80x94H, C1-6alkyl, C1-6alkanoyl, C1-6alkoxycarbonyl, aryl, (aryl)C1-6alkyl, arylcarbonyl, or aryloxycarbonyl, and R10 is as defined above, comprising:
a) coupling a compound of the formula (7) prepared in accordance with the above description and as illustrated herein: 
xe2x80x83with a compound of the formula (6): 
xe2x80x83wherein R6, R8 and R9 are each independently a hydroxyl protecting group, and xe2x80x94OR7 is a leaving group, that is, a displaceable group which can be substituted by another group or molecule, such as by the secondary alcohol (xe2x80x94OH) functional group of compound (7), and without inversion of the stereochemistry on the sugar ring carbon to which xe2x80x94OR7 is attached, to form a compound of the formula (36); and 
b) deprotecting the compound of formula (36) to afford the compound of formula (1).
In embodiments, the aforementioned R1 as a hydroxyl protecting group can be, for example, of the formula xe2x80x94Si(R12)3 wherein each R12 can be independently C1-4 alkyl, such as xe2x80x94Me, xe2x80x94Et, and the like. The Ar of xe2x80x94C(xe2x95x90O)xe2x80x94Ar can be independently an aryl or a heteroaryl group, optionally substituted with one or more substituents selected independently from, for example, halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCF3, methylene dioxy, C1-6alkyl, C1-6alkoxy, phenyl, NRcRd, or xe2x80x94C(xe2x95x90O)NRcRd; wherein each Rc and Rd is independently xe2x80x94H, C1-6alkyl, C1-6alkanoyl, C1-6alkoxycarbonyl, aryl, (aryl)C1-6alkyl, arylcarbonyl, aryloxycarbonyl, or like groups; or Rc and Rd together with a nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; or a pharmaceutically acceptable salt thereof.
The Ar of xe2x80x94C(xe2x95x90O)xe2x80x94CRcxe2x95x90CRdxe2x80x94Ar can independently be an aryl or a heteroaryl group and wherein any aryl or heteroaryl can be optionally substituted with one or more substituents independently selected from halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCF3, methylene dioxy, C1-6alkyl, C1-6alkoxy, phenyl, NRcRd, xe2x80x94C(xe2x95x90O)NRcRd, and like groups; wherein each Rc and Rd can be independently hydrogen, C1-6alkyl, C1-6alkanoyl, C1-6alkoxycarbonyl, aryl, (aryl)C1-6alkyl, arylcarbonyl, aryloxycarbonyl, or like groups; or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino ring, and like groups; or a pharmaceutically acceptable salt thereof. In embodiments, R2 can be independently p-methoxybenzoyl, 3,4-dimethoxybenzoyl, (E)-cinnamoyl, or (Z)-cinnamoyl, and like groups.
Preferred R1 and R2 groups in the compound of the formula (1) are where R1 is xe2x80x94H, and R2 is p-methoxybenzoyl, and which compound corresponds to OSW-1 wherein R10 is xe2x80x94CH2xe2x80x94CH(CH3)2. The 1,4-addition activating agent can be, for example, a trialkylsilylchloride, such as trimethylsilylchloride. The R3 enolic hydroxyl protecting group can be, for example, an alkyl group and like groups, and preferably a bulky alkyl or cycloalkyl group, such as, C5-7cycloalkyl, and the R4 enolic hydroxyl protecting group can be, for example, alkanoyl, such as acetyl, and like groups.
The selective deprotection of indicated hydroxyl groups to afford the compound of formula (1) can be accomplished by sequentially treating the compound of formula (36) with DDQ and thereafter bis-(acetonitrile)dichloropalladium(II). The compound of the formula (9) can be prepared by the steps comprising, for example:
a) olefinating the ketone of the compound of formula (14), for example, with an appropriate Wittig reagent, like olefin producing ylid modification reagents, and like reagents or equivalent reagents which produce an olefin product being compatible with the R1 protecting group; 
b) allylicly oxidizing the resulting olefin compound to form an allylic alcohol compound of formula (15); and 
c) oxidizing the allylic alcohol (15) to form a 1,4-enone compound of formula (9) 
The compound of the formula (6): 
can be prepared by the steps comprising:
a) glycosylating a compound of the formula (25) 
wherein R6 is a hydroxyl protecting group, that is, suitable for protection and deprotection of a secondary hydroxyl group in a simple sugar or a similarly substituted pyranose ring system, and X can be, for example, an SN1 leaving group, that is for example, a group which is capable of selective substitution or conversion to an xe2x80x94OR7 leaving group and without stereochemical inversion at the sugar ring carbon. For example, X can be xe2x80x94SAr wherein Ar is, for example, phenyl. Compound 25 can be glycosylated, for example, by reaction with a compound of the formula (34) 
wherein xe2x80x94OR11 is preferably a leaving group of the formula xe2x80x94OC(xe2x95x90NH)CCl3, to afford a compound of the formula (35): 
b) X is then converted into a leaving group xe2x80x94OR7 of the formula, for example, xe2x80x94Oxe2x80x94C(xe2x95x90NH)CCl3 to afford the above compound of formula (6). The leaving group X can be, for example, xe2x80x94SAr wherein Ar is as defined above, such as phenyl, and like substituents.
The present invention also provides novel intermediates and processes as disclosed herein that are useful for preparing compounds of formula (1).
Applicants have discovered a new and efficient convergent strategy for the total synthesis of OSW-1 and related saponin compounds including direct introduction of the complete carbon side chain of OSW-1 steroid precursors as shown in Scheme 1. 
A retrosynthetic analysis is shown in Scheme 2. OSW-1 (1) was conceptually disconnected into the disaccharide 6 and the steroid aglycone 7. Compound 7 was viewed as obtainable by 1,4-addition of the R-alkoxy vinyl cuprate 8 to compound 9 which compound was prepared from commercially available 5-androsten-3xcex2-ol-17-one 10. 
Scheme 3 outlines the synthesis of the R-alkoxy vinyl cuprate 8. The acetylenic ether 11 was prepared according to the literature procedure.13 The xcex1-bromo vinyl ether 13 was prepared regio- and stereoselectively according to literature procedures,7 which was in turn converted in situ to a high-order cuprate 8.14 
Compound 15 was prepared from 10 according to literature procedure as shown in Scheme 4.15 
Trost and co-workers have shown that selenium dioxide-mediated allylic oxidation can regio- and stereoselectively introduce a hydroxy group into the C-16 of the steroid 17(20)-en-16-ones.15 However, in their examples the double bond in the B ring was protected. The present invention achieves complete chemo-, regio-, and stereoselective allylic oxidation at C-16 under the same reaction conditions without the protection of the 5(6) double bond.
Swern oxidation of 16 afforded enone 9 in nearly quantitative yield.15 TMSCl-activated8 1,4-addition of R-alkoxy vinyl cuprate 8 to enone 9 gave silyl enol ether intermediate 17, which was converted to enol acetate 18 in a single operation without the isolation of 17.16 The conversion of silyl enol ether 17 to enol acetate 18 enabled chemoselective transformation of the enol ether to cyclic acetal 19. Generation of the enolate from 19 by potassium ethoxide or potassium tert-butoxide17 followed by in situ oxidation by Davis reagent18 stereoselectively gave R-hydroxy ketone 20 in 76% yield. Stereoselective reduction of compound 20 by LiAlH4 at xe2x88x9278xc2x0 C. provided the requisite trans-16xcex2,17xcex1-diol 7 in 97% yield.19 Thus, the protected aglycone of OSW-1 (1) was synthesized with eight operations in 48.4% overall yield.
Synthesis of the disaccharide 6 is outlined in Schemes 5, 6, and 7. Thioglycoside 22 was prepared from tetraacetyl-L-arabinose 21 as shown in Scheme 5. 
Regioselective protection of the cis-diol 22 followed by protection of the C-2 hydroxy group gave 23 in 90% yield. Deprotection of the acetonide afforded diol 24. Although it is known that the equatorial C-3 hydroxy group in many sugars is more reactive than C-4 axial hydroxy group, surprisingly high selectivity at the C-4 hydroxy group was observed when 24 was treated with TESOTf and lutidine at low temperature affording the desired product 25 in 90% yield.
The thio ortho ester 28 was prepared from tetraacetyl-D-xylose 26 as shown in Scheme 6.20 
Protecting-group manipulations followed by zinc chloride promoted intramolecular ring-opening of the thio ortho ester 30 gave thioglycoside 31 in excellent yield. After deacetylation, the p-methoxy benzoyl group was introduced, and 33 was converted to 34 in 84%.21 
Glycosylation of 25 with 34 afforded the xcex2-disaccharide 35 which was converted to 6 as shown in Scheme 7. 
Coupling of 6 with the steroid aglycone 7 under standard conditions22 gave compound 36 in 71% yield. Removal of all of the protecting groups by sequential treatment of compound 36 with DDQ and bis-(acetonitrile)dichloropalladium(II) in one operation afforded OSW-1 (1) in 81% yield. The physical data of synthetic OSW-1 (1) were identical to those reported by Sashida.10 
The new strategy provides stereoselective introduction of the steroid side chain via 1,4-addition of an xcex1-alkoxy vinyl cuprate to 17(20)-en-16-one steroids. On the basis of the strategy, the highly potent anti-tumor natural product OSW-1 (1) was synthesized in 10 linear operations from 10 in 28% overall yield.
Additional supporting experimental information, such as spectral characterizations, is available at http://pubs.acs.org. The foregoing literature references of this section are listed below.
7) Yu, W.; Jin, Z. J. Am. Chem. Soc., 122, 9840, 2000.
8) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett., 26, 6019, 1985.
(b) Alexakisss, A.; Berlan, J.; Besace, Y. Tetrahedron Lett., 27, 1047, 1986.
10) Kubo, S.; Mimaki, Y.; Terao M.; Sashida, Y.; Nikaido, T.; Ohmoto, T. Phytochemitstry, 31, 3969, 1992.
12) (a) Guo, C.; Fuchs, P. Tetrahedron Lett., 39, 1099, 1998. (b) Deng, S.; Yu, B.; Lou, Y.; Hui, Y. J. Org. Chem., 64, 202, 1999. (c) Morzycki, J. W.; Gryszkiewicz, A.; Jastrzebska, I. Tetrahedron Lett., 41, 3751, 2000.
13) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem., 52, 2919, 1987.
14) Lipshutz, B. H. Synthesis, 87, 325, 1987, and references therein.
15) Schmuff, N. R.; Trost, B. M. J. Org. Chem., 48, 1404, 1983.
16) The stereochemistry at C-16 and C-17 of compound 7 was determined by NOESY spectra.
17) Nicolaou, K. C.; Trujillo, J. I.; Chibale, K. Tetrahedron, 53, 8751,1997.
18) Yu, W.; Jin, Z. Tetrahedron Lett., 42, 369, 2001.
19) Duhamel, P.; Cahard, D.; Poirier, J. M. J. Chem. Soc., Perkin Trans. 1, 21, 2509, 1993.
20) Davis, F. A.; Sheppard, A. C. Tetrahedron, 45, 5703, 1989.
21) Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft, F. L.; Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kimet, S. J. Am. Chem. Soc., 120, 8674, 1998.
22) Jiang, Z. H.; Schmidt, R. R. Liebigs Ann. Chem., 975, 1992.
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, and the like, denote both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more, for example, 1, 2, 3, or 4, double or triple bonds in the chain.
Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl denotes a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C1-4alkyl, phenyl, or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms, for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase, and how to determine anticancer activity using the standard tests which are well known in the art.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, that is, the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-6alkyl refers to alkyl of one to six carbon atoms, inclusive.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used, for example, xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, C1-4alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, and all isomers thereof; C1-6alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, and all isomers thereof; C1-6alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, and all isomers thereof; C1-6alkanoyl can be, for example, acetyl, propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl, and all isomers thereof; C1-6alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, and all isomers thereof; C1-6alkanoyloxy can be, for example, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, hexanoyloxy, and all isomers thereof; aryl can be, for example, phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl or its N-oxide, thienyl, pyrimidinyl or its N-oxide, indolyl, isoquinolyl or its N-oxide, or quinolyl or its N-oxide, and all isomers thereof.
A specific value for R1 is xe2x80x94H
Another value for R1 is a hydroxyl protecting group.
A specific value for R1 is of the formula xe2x80x94Si(R12)3 wherein each R12 can be independently C1-4 alkyl.
A more specific value for R1 is xe2x80x94Si(CH3)3.
Another specific value for R1 is xe2x80x94Si(C4H9)3.
A specific value for R2 is hydroxyl protecting group.
A more specific value for R2 is aroyl of the formula xe2x80x94C(xe2x95x90O)xe2x80x94Ar.
A more specific value for R2 is p-methoxybenzoyl.
Another value for R2 is xe2x80x94C(xe2x95x90O)xe2x80x94CRcxe2x95x90Cdxe2x80x94Ar.
A more specific value for R2 is (E)-cinnamoyl.
Another specific value for R2 is (Z)-cinnamoyl.
A specific value for R3 is a hydroxyl protecting group.
A more specific value for R3 is alkyl.
Another more specific value for R3 is cycloalkyl.
Another more specific value for R3 is C6cycloalkyl, that is, cyclohexyl.
A specific value for R4 is an enolic hydroxyl protecting group.
A more specific value for R4 is an alkanoyl.
Another more specific value for R4 is acetyl.
Another more specific value for R4 is propanoyl.
Another more specific value for R4 is butanoyl.
A specific value for R6 is a hydroxyl protecting group
A more specific value for R6 is an xe2x80x94C(xe2x95x90O)xe2x80x94Ar.
Another more specific value for R6 is a benzoyl.
Another more specific value for R6 is a mono-methoxy substituted benzoyl.
Another more specific value for R6 is a di-methoxy substituted benzoyl.
Another more specific value for R6 is p-methoxy substituted benzoyl.
A specific value for X is a leaving group
A more specific value for X is xe2x80x94SAr.
Another more specific value for X is xe2x80x94SPh.
A specific value for xe2x80x94OR7 is a leaving group.
A more specific value for xe2x80x94OR7 is an acetamidate.
Another more specific value for xe2x80x94OR7 is xe2x80x94OC(xe2x95x90NH)CCl3.
A specific value for R8 or R9 is a hydroxyl protecting group.
A more specific value for R8 or R9 is an xe2x80x94C(xe2x95x90O)xe2x80x94Ar.
Another more specific value for R8 or R9 is a benzoyl.
Another more specific value for R8 or R9 is a mono-methoxy substituted benzoyl.
Another more specific value for R8 or R9 is a di-methoxy substituted benzoyl.
Another more specific value for R8 or R9 is p-methoxy substituted benzoyl.
A specific value for R10 is C2-12 alkyl.
A more specific value for R10 is xe2x80x94CH2xe2x80x94CH(CH3)2.
A specific value for xe2x80x94OR11 is a leaving group.
A more specific value for xe2x80x94OR11 is an acetamidate.
Another more specific value for xe2x80x94OR11 is xe2x80x94OC(xe2x95x90NH)CCl3.
The invention also provides processes and intermediates useful for preparing compounds of formula (1). For example, intermediates useful for preparing a compound of the formula (1) wherein R1 is hydrogen and R2 is an aroyl or a cinnamoyl group, or a corresponding compound of the formula (1) wherein R1 is a suitable protecting group, such as trialkylsilane. Thus the invention provides a compound of formula (1) wherein R2 is both a suitable protecting group and is also desired in the final product such as an aroyl or a cinnamoyl group. Suitable protecting groups as used herein, as well as methods for their preparation and removal, are well known in the art, for example, see Greene, T. W.; Wutz, P. G. M. xe2x80x9cProtecting Groups In Organic Synthesisxe2x80x9d 3rd edition, 1999, New York, John Wiley and sons, Inc.
The invention also provides intermediate compounds, for example, of the formulas 6, 7, 9, 15, 18, 20, 25, 34, 35, and 36, among others, and as shown in accompanying preparative schemes hereinafter.
The invention also provides intermediate salts that are useful for preparing or purifying compounds of formula (1). Suitable methods for preparing salts are known in the art and are disclosed herein. As will be apparent to one skilled in the art, such salts can be converted to the corresponding free-base or to another salt using known methods.
The invention also provides a method for preparing a compound of formula (1) wherein R1 is hydrogen comprising deprotecting a corresponding compound of formula (1) in the presence of a second protecting group R2 wherein both R1 and R2 are suitable protecting groups, and as illustrated herein.
Compounds of the invention can generally be prepared using the illustrated synthetic schemes. Starting materials can be prepared by procedures described in these schemes, the accompanying experimental examples, or by procedures well known to one of ordinary skill in organic chemistry. The variables used in the schemes are as defined below or as in the claims.
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, xcex1-ketoglutarate, and xcex1-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal, for example, sodium, potassium or lithium, or alkaline earth metal, for example calcium, salts of carboxylic acids can also be made.
Useful dosages of the compounds of formula (1) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The following examples in conjunction with the accompanying schemes and references provide illustrative and representative synthetic procedures for preparing compounds of the formula (1) and intermediate compounds leading thereto.